Neuropathic pain is a chronic pain state caused by injury of the nervous system, and there are various conditions associated with it such as diabetic neuropathy, postherpetic neuralgia, cancer pain, trigeminal neuralgia, cervical radiculopathy, and anticancer and anti-HIV-induced neuropathic pain. The pathophysiological role of voltage-gated T-type calcium channels in neuropathic pain has been well documented. ABT-639 is a peripherally acting, selective T-type calcium channel blocker, and it is shown to efficiently reduce nociceptive and neuropathic pain in rats in multiple models. However, three clinical studies exploring the role of single dose or multiple doses of ABT-639 (100 mg) in diabetic neuropathy have not found significant pain-attenuating actions. The present review discusses the unsuccessful clinical trials of peripherally acting ABT-639 in patients with diabetic neuropathy.

Neuropathic pain is a pain associated with damage to the somatosensory nervous system with symptoms such as pricking of needles, burning or coldness, numbness, dysesthesia (abnormal sensations), allodynia (pain from normally nonpainful stimuli), and hyperalgesia (increased sensitivity to pain).[1] There are various conditions associated with neuropathic pain such as diabetic neuropathy, postherpetic neuralgia, cancer, trigeminal neuralgia, anticancer and anti-HIV-induced neuropathic pain, and cervical radiculopathy.[2] At present, clinically approved drugs for neuropathic pain management include antidepressants,[3] anticonvulsants,[4] N-methyl-D-aspartate receptor antagonists,[5] topical and local anesthetics,[6] nonsteroidal anti-inflammatory drugs,[7] opioids, and corticosteroids.[8] Apart from these, there are other targets exploited in preclinical studies such as ion channel blockers (calcium, sodium, potassium, and transient receptor potential channels;[9] ion exchange modulators;[10] and enzyme inhibitors).[11] However, the existing pharmacotherapy has marginal efficacy and significant side effects, and there is a need to identify more efficacious neuropathic pain-attenuating drug.

Calcium channels play an important physiological role in neuronal excitability, vasodilation, myogenic response, and mitochondrial calcium signaling.[12] These channels also have pathophysiological role in Alzheimer disease, multiple sclerosis, diabetes, cardiovascular diseases, and leprosy.[13] Voltage-gated calcium channels (VGCCs) may be classified into the following five subtypes: L-type, N-Type, P-type, T-type, and R-type.[14],[15] These VGCCs are widespread in the different body parts including nerves, brain, dorsal root ganglia (DRG), spinal cord, heart, and vascular smooth muscles.[16] Among these, voltage-gated T-type calcium channels are widespread in the brain, spinal cord, DRG, and nerves.[17]

A number of preclinical studies have shown the role of T-type calcium channels in the pathogenesis of neuropathic pain. It has been shown that the activation of T-type calcium channels in DRG produces neuropathic pain in a paclitaxel model.[17] Moreover, spinal nerve ligation has been shown to upregulate the expression of T-type calcium channels in the DRG region.[18] In spared nerve injury model, it has been shown that accumulated ions of T-type calcium channels in the uninjured sural nerve contribute to neuropathic pain in rats.[19] Functional role of T-type calcium channels in pain signaling has also been described.[20] It has been revealed that the demethylation of voltage-gated T-type calcium channel 3.2-subunit induced by DNA damage, enhances allodynia after nerve injury in rats.[21]In vivo silencing of the Ca (v) 3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in streptozocin-induced diabetic neuropathy in rats.[22] A randomized, parallel, controlled, double-blinded, and multicentric clinical trial has shown the effectiveness and safety of ethosuximide in the treatment of nondiabetic peripheral neuropathic pain.[23] The present review discusses the role of a selective, peripherally acting T-type calcium channel blocker, ABT-639, in neuropathic pain.

ABT-639 in Preclinical Studies

ABT-639 is a peripherally acting, selective T-type calcium channel blocker, and it is shown to efficiently reduce nociceptive and neuropathic pain in rats in multiple models [24] Following acute oral administration (3–100 mg/kg), ABT-639 was shown to produce dose-dependent attenuation of mechanical hypersensitivity (assessed 60 min after its administration) in the spinal nerve ligation model and in vincristine (30 mg/kg/day vincristine sulfate) chemotherapy-induced neuropathic pain models. Moreover, ABT-639 (3–100 mg/kg, p.o.) also produced the attenuation of mechanical and cold allodynia (assessed 60 min after its administration) in the chronic constriction injury model of neuropathic pain and complete Freund's adjuvant model. Furthermore, in monoiodoacetic acid (MIA)-induced knee joint pain model (MIA) of osteoarthritic pain, acute administration of ABT-639 (3, 10, and 30 mg/kg) produced a dose-dependent reversal of pain as well as restored force deficit. Thus, it may be suggested that ABT-639 has the potential to attenuate pain of diverse types including neuropathic pain in rats.

Lack of Efficacy of ABT-639 in Clinical Studies

There are various clinical studies exploring the therapeutic potential of ABT-639 in neuropathic pain.[25],[26] Wallace et al. explored the pain-attenuating effects of ABT-639 in humans in an intradermal capsaicin pain model in Phase 1, single-dose, double-blinded, randomized, crossover study using pregabalin as a positive control. Nineteen adult male volunteers (21–55 years old) were involved in this study. One volunteer left the study due to a military deployment; therefore, rest of the 18 volunteers received the complete drug regimen. To minimize the role of fluctuations in hormonal levels on pain response, only male participants were included in this study. All the study procedures were proficiently completed at the University of California San Diego Medical Center, La Jolla, CA, from February 29, 2012, to May 29, 2012. Treatment groups received identical capsules of 100 mg ABT-639, 300 mg of pregabalin, or placebo. Participants under the fasting conditions received each dose orally with water. Participants were given first capsaicin injection (250 mg) 1 h after taking ABT-639 dose to match the time corresponding to the maximum plasma exposure (tmax) of ABT-639, and the second injection was given after 4 h to evaluate hysteresis in pharmacodynamic effect relative to plasma exposure. Pain was measured using a 100-mm Visual Analog Scale at prespecified intervals (5, 10, 15, 20, 30, 40, 50, and 60 min) over a 60-min period after each capsaicin injection. Unlike pregabalin, a single 100-mg dose of ABT-639 had no effect on spontaneous or elicited pain in the intradermal capsaicin model used in this study. Moreover, there were no significant differences in response between 100 mg ABT-639 and placebo, thereby documenting that a single dose of ABT-639 does not relieve pain in capsaicin pain models in humans.[25]

Ziegler et al. compared the analgesic efficacy and safety of ABT-639 with placebo in diabetic patients with peripheral neuropathic pain for 6 weeks in Phase 2, multicenter, randomized, double-blinded, placebo-controlled, active-controlled, parallel-group study. Both male and female patients (18–75 years) with a diagnosis of diabetic peripheral neuropathy (diabetes mellitus type 1 or type 2) for at least 6 months were included in this study. A total of 194 patients from approximately forty sites in North America and Europe were included. Seventeen patients discontinued the study prematurely. The most common reason for discontinuation was adverse events, that is, abdominal distension, muscle spasms, viral gastroenteritis, insomnia, nasopharyngitis, rashes, and sinusitis. Other causes for discontinuation included withdrawal of (n = 6) consent, lack of efficacy (n = 2), lost to follow-up (n = 1), and other reasons (n = 3). Out of the 194 patients, 62 patients were administered ABT-639, 70 patients were given pregabalin, and 62 patients received placebo. On day 1, patients received a blinded kit of the study drug (ABT-639, placebo, or pregabalin) and were guided to take drug twice daily (12 h apart), that is, ABT-639 100 mg (2 × 50-mg capsules), pregabalin 75 mg (1 × 75-mg capsule and one placebo capsule), or placebo (two capsules). Scoring of pain was done on the basis of a 11-point Numeric Rating Scale, where 0 = no pain and 10 = worst pain imaginable. However, repeated treatment with ABT-639 did not significantly affect pain score, and there was no significant difference from day 1 to the final day on 24-h average pain score in patients treated with ABT-639 and patients receiving placebo. It also suggests the lack of efficacy of ABT-639, even on repeated administration, in attenuating pain in diabetic neuropathy.[26]

Serra et al. conducted a study to assess the effects of ABT-639 and lidocaine on spontaneous pain activity in Phase 2, double-blinded, parallel-group, randomized, placebo-controlled study in patients with painful diabetic peripheral neuropathy. Men and women (18–75 years) with diabetic neuropathy for at least 6 months were randomized for the studies. Treatment regimen included the ABT-639 treatment group, which received ABT-639 (two 50-mg capsules orally) and placebo (glucose) infused intravenously (IV) over 30 min; the lidocaine treatment group, which received placebo (two capsules orally) and lidocaine 3 mg/kg IV infused over 30 min; and the placebo group, which received placebo (two capsules orally) and placebo (glucose) IV infused over 30 min. Treatment was given under fasting conditions, and IV infusion was given 30 min after the oral dose. Pain assessment was done at three different time segments, that is, first 30 min, 30–90 min, and after 90 min. However, there were no statistically significant differences between ABT-639, lidocaine, and placebo-treated patients in terms of improvements in spontaneous pain activity, and there were no meaningful differences in pain intensity scores.[27]

Pharmacokinetics of ABT-639

An et al. studied the pharmacokinetics of ABT-639 in healthy human subjects. One hundred and twenty-four individuals were enrolled in the study at the Abbott Clinical Pharmacology Research Unit, Vista Medical Center (Waukegan, IL, USA). Both male and female volunteers (18–55 years) for parts I–III and volunteers of age at least 65 years for Part IV were included in the study. Part I study was a single-dose, double-blinded, randomized, placebo-controlled, escalating-dose study design conducted on healthy adults. ABT-639 was administered orally under fasting condition. Forty individuals participated in this study in five dose groups (10, 30, 60, 100, and 170 mg of ABT-639). In each group, eight participants were randomized such that six participants received ABT-639 and two participants received placebo. Venous blood samples were collected within 10 min before oral dosing (0 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 36, 48, 60, 72, 95, and 120 h after oral dosing.

In part II, the effect of food on ABT-639 (50 mg) in each period was investigated in a randomized, single-dose, open-label, and two-period crossover manner. Twelve individuals participated in this study, and the blood samples were collected using the same sampling scheme as that in Part I. Part III was a multiple-dose, double-blinded, randomized, placebo-controlled, escalating-dose approach in healthy adults, and ABT-639 was administered orally 30 min after breakfast. Forty-eight individuals participated in this study in four dose groups (10, 40, 100, and 160 mg), and ABT-639 was administered twice daily. In each group, 12 participants were randomized such that nine participants received ABT-639 and three participants received placebo for 7 days (10, 40, and 100 mg BID dose groups) or 14 days (160 mg BID dose group). For the 10, 40, and 100 mg BID dose groups, blood samples were collected within 10 min prior to morning dosing on study day 1 at 0 h (morning dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 h; on study days 5 and 6 at 0 h (prior to morning dose); and on study day 7 at 0 h (prior to morning dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 (prior to evening dose), 12.5, 13, 13.5, 14, 15, 16, 18, 21, 24, 36, 48, 60, 72, and 96 h. For the 160-mg BID dose group, in addition to the above-mentioned samples, blood samples were collected on study days 12 and 13 at 0 h (prior to morning dose) and on study day 14 at 0 h (prior to morning dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 (prior to evening dose), 12.5, 13, 13.5, 14, 15, 16, 18, 21, 24, 36, 48, 60, 72, and 96 h. Part IV included a multiple-dose, double-blinded, randomized, placebo-controlled study in healthy elderly individuals. Twenty-four individuals participated in this study in two dose groups (40 and 160 mg of ABT-639 BID). In each group, 12 participants were randomized such that eight participants received ABT-639 and four participants received placebo for 7 days. Blood and urine samples were collected using the same sampling scheme as that in part III.

The results revealed the diurnal effect of ABT-639, and there was a difference in the plasma levels on its administration in the morning or in the evening, which may be possibly due to the ingestion of food. There was a complete metabolism of ABT-639 in the body and therefore, the excretion of unchanged drug (ABT-639) through urine was minimal. However, no statistically significant difference was found between the elderly and adults in any of the pharmacokinetic parameters evaluated. Interestingly, the blood uric acid concentrations were significantly decreased in a dose-dependent manner on administration of ABT-639. This unexpected and interesting phenomenon indicated that ABT-639 may represent a potential candidate not only in the treatment of chronic pain, but also in the treatment of hyperuricemia and its complications, chronic gout.[28]

Discussion

Preclinical as well as clinical studies have shown that T-type calcium channels are important in the pathogenesis of neuropathic pain.[18],[17] Preclinical studies on ABT-639, a peripheral T-type calcium channel blocker, also depicted potent neuropathic pain-attenuating effects in different models of pain.[24] However, contrary to preclinical studies, three clinical studies exploring the beneficial role of ABT-639 in neuropathic pain failed to find the pain-attenuating actions of ABT-639 in patients with diabetic neuropathy. The lack of neuropathic pain-attenuating effects of ABT-639 in the study of Wallace et al. may be possibly due to a number of factors. The dose selection may be an important limiting factor. Although the 100-mg oral dose of ABT-639 was predicted to be efficacious based on preclinical data, yet it is possible that the higher dose may be effective in patients. Moreover, in this study, a single-dose trial of ABT-639 (a single dose of 100 mg dose) was employed, which may also be an important limiting factor. The authors also suggested that the number of patients (n = 19) may be low enough to deduce the positive results of the drug.[25] The clinical study of Serra et al. also employed a single dose (100 mg) of ABT-639 in diabetic neuropathy with lidocaine as a positive control, with no beneficial effect observed on the pain symptoms. The same explanation of using a single dose of 100 mg may be given to explain the nonefficacy of ABT-639. However, the nonefficacy of lidocaine (positive control) raises the question of validity of the study.[27] However, Ziegler et al. failed to document the pain-attenuating actions of 100 mg of ABT-639 even after its 6 months of treatment, suggesting that even repeated administration of ABT-639 is not sufficient to attenuate pain in diabetic neuropathy.

The nonefficacy of ABT-639 may be ascribed to a number of factors as follows:

The dose of 100 mg may not be sufficient to produce the desired therapeutic effect. Since ABT-639 is a peripherally acting drug and the development of central sensitization is critical in the development of neuropathic pain symptoms, the lack of its central actions may be also responsible for its noneffectiveness in attenuating neuropathic pain

Another T-type calcium channel blocker, Z944, which is relatively less selective and more centrally acting, has shown reduction in pain scores in human experimental pain models as well as in preclinical studies.[27],[29] All the three clinical studies related to ABT-639 have been done in diabetic neuropathy. It may be possible that this drug may not be effective in diabetic neuropathy; rather, it may be effective in other types of neuropathic pain conditions.

Conclusion

Although peripherally acting, selective T-type calcium channel blocker, ABT-639, has shown efficacy in attenuating neuropathic pain in preclinical studies, yet no significant results were observed in three clinical trials in patients with diabetic neuropathy. However, selective T-type calcium channel blockers as a target for neuropathic pain management should not be discarded without further investigations.